Cells adhere to other cells and to substrates through specific, regulated processes that are critical to various biological functions. The proper functioning of the immune system is dependent upon adhesive interactions and cell migration. A key event in an immune response involves the migration of leukocytes to a disease site. During an inflammatory response, leukocytes are recruited to the site of injury and extravasated by a series of cellular interactions involving cell-cell and cell-substrate adhesion.
One family of molecules that serves an important adhesive function is integrins. Integrins are expressed on cell surfaces and function in cell-cell and cell-substrate adhesion. Integrins are alpha-beta heterodimers: each integrin has an alpha (α) subunit non-covalently bound to a beta (β) subunit. When activated, integrins bind to extracellular ligands and induce adhesion (the expression of integrins on a cell surface alone is inadequate for adhesion—they must be activated to become adhesive). The integrin activation state is transient, such that there is a rapid flux between adhesive and non-adhesive states which is important for cell movement, e.g., a cell is endowed with the ability to rapidly adhere to various cell surfaces and matrices and to migrate among cells and tissue.
There are four known integrins having a β2 or CD18 subunit which comprise the CD11/CD18 integrin sub-family, namely, Lymphocyte Function-associated Antigen 1 (LFA-1) (CD11a/CD18 or αLβ2); Macrophage Antigen 1 (Mac-1) (CD11b/CD18 or αMβ2); p150,95 (CD11c/CD18 or αXβ2); and αDβ2. The CD11/CD18 family of integrins is also referred to as Leukointegrins as they are expressed on the surface of various leukocyte cells, and they mediate a number of inflammation-related cellular interactions. See Diamond et al., “The Dynamic Regulation of Integrin Adhesiveness,” Current Biology, Vol. 4 (1994) at pp. 506-532.
Ligands to LFA-1 and Mac-1 comprise the intercellular adhesion molecule (ICAM) ICAM-1. The primary CD11/CD18 integrin is LFA-1, which also binds with ICAM-2 and ICAM-3. ICAMs are found on endothelium cells, leukocytes, and other cell types, and their interaction with CD11/CD18 integrins is critical to immune system function. The interaction between the CD18 integrins, particularly LFA-1, and ICAMs mediates antigen presentation, T-cell proliferation, and adhesion between the endothelium and activated leukocytes which is necessary for leukocytes to migrate from the circulatory system into tissue. A condition termed “Leukocyte Adhesion Deficiency” has been identified in patients having a deficiency in CD18 integrins. These patients are unable to mount a normal inflammatory or immune response; they suffer from disorders such as recurrent infections, poor wound healing, granulocytosis, progressive periodontitis, and umbilical cord separation. See Anderson et al., “Leukocyte LFA-1, OKMI, p150,95 Deficiency Syndrome: Functional and Biosynthesis Studies of Three Kindreds,” Fed. Proc., Vol. 44 (1985), at pp. 2671-2677.
While sufficient levels of CD18 integrins interacting with ICAMs are needed to mount a normal immune response, significant cellular and tissue injury can result in chronic inflammatory states where there is an inappropriate influx of leukocytes to the disease site. Continuous recruitment of leukocytes from blood vessels into inflamed tissue, as in chronic inflammatory states, can perpetuate tissue injury and lead to excessive fibrous repair and autoimmune disease. Thus, inhibition of the interaction between LFA-1 and/or Mac-1 and their ICAMs can be advantageous in treating inflammatory or immune disease. For example, monoclonal antibody blockade of either ICAM or LFA-1 has been shown to prevent the migration of leukocytes into tissue and the subsequent development of inflammatory disease in animal models of rheumatoid arthritis, inflammatory bowel disease, and pulmonary inflammation (e.g., asthma). Knockout mice deficient in ICAMs have reduced susceptibility to induced arthritis, ischemia injury, impaired lung inflammatory responses, and increased tolerance to transplantations (e.g. heart grafts). See Anderson, supra. Antibodies blocking the ICAM-LFA-1 interaction reportedly suppress cardiac allograft rejection and islet cell xenograft rejection in animal models. See Gorski, “The Role of Cell Adhesion Molecules in Immunopathology,” Immunology Today, Vol. 15 (1994), at pp. 251-255.
Compounds inhibiting CD18 integrins, ICAMs, and/or the LFA-1:ICAM interaction could potentially demonstrate a wide range of utilities in treating inflammatory or immune diseases. Blocking LFA-1 reportedly inhibits the influx of leukocytes in almost every system, including the skin, peritoneum, synovium, lung, kidney, and heart, and blocking ICAM-1 would be expected to have similar effects. Also, present therapies for many inflammatory and immune diseases have drawbacks. For example, current treatments for asthma include β2-agonists, inhaled corticosteroids, and LTD4 antagonists. However, β2-agonists have limited efficacy and inhaled corticosteroids raise safety concerns. To treat psoriasis, current therapies include PUVA, methotrexate, cyclosporin A, and topical treatments. The first three of these therapies raise toxicity issues over long-term (e.g., 6-9 month) use, whereas topical treatments have limited efficacy. Additionally, these treatments typically are applied only in response to flares and not as a prophylaxis measure.
Compounds that reportedly inhibit LFA-1/ICAM for use as anti-inflammatory agents include thiadiazole-based compounds (see Intern. Pub. No. WO 99/20,618, “Thiadiazole Amides Useful as Anti-Inflammatory Agents” filed by Pharmacia & Upjohn Co.; and WO 99/20,617, also to Pharmacia and Upjohn); and thiazole compounds linked to phenyl and pyrazole rings (Sanfilippo et al., “Novel Thiazole Based Heterocycles as Inhibitors of LFA-1/ICAM-1 Mediated Cell Adhesion,” J. Med. Chem., Vol. 38 (1995) at pp.1057-1059). Small molecules that reportedly are antagonists to the binding of ICAMs with CD18 integrins include various benzylamines and 2-bromobenzoyltryptophan compounds (see Intern. Pub. No. WO99/49,856, “Antagonists for Treatment of CD11/CD18 Adhesion Receptor Mediated Disorders,” filed by Genentech, Inc.), and 1-(3,5 dichlorophenyl)imidazolidines (see Intern. Pub. No. WO98/39303, “Small Molecules Useful in the Treatment of Inflammatory Disease,” filed by Boehringer Ingelheim Pharmaceuticals, Inc. See also Boehringer patent applications WO 01/07052, WO 01/07048, WO 01/07044, WO 01/06984, and WO 01/07440). Hydantoin compounds are disclosed in Intern. Pub. No's WO 00/59880, WO 00/39081, WO 02/02522, WO 02/02539 (all to Abbott Laboratories). LFA-1 antagonist compounds are also claimed in WO 02/059114 (to Genentech), WO 02/42294 (to Celitech), WO 01/51508 (to Science and Technology corporation), WO 00/21920 and WO 01/58853 (both to Hoffmann-LaRoche), WO 99/11258, WO 00/48989 and WO 02/28832 (all to Novartis). Hydantoin compounds are disclosed in Intern. Pub. No. WO 01/30781 A2 (published May 3, 2001) to Tanabe Seiyaku Co. Ltd, “Inhibitors of αLβ2 Mediated Cell Adhesion,” and in Intern. Pub. No. WO 02/44181 (published Jun. 6, 2002),“Hydantoin Compounds Useful as Anti-Inflammatory Agents”, to the present assignee and having common inventors herewith.
As may be appreciated, those in the field of pharmaceutical research continue to develop new compounds and compositions for treating inflammatory and immune disease such as inhibitors of Leukointegrins and/or ICAMs. Particularly in the area of immune response, many individuals respond differently to different drugs. Thus, there is an interest in providing consumers not only with pharmaceutical compositions demonstrating increased effectiveness and reduced side-effects but also different structures or mechanisms of action to provide consumers with a choice of options. The instant invention is directed to aryl or heteroaryl substituted spiro-hydantoin compounds that are effective as antagonists of Leukointegrins and/or ICAMs. Diazaspiroheptane compounds are disclosed in Park et al., “Preparation of a 990 Member Chemical Compound Library of Hydantoin and Isoxazoline-Containing Heterocycles Using Multipin Technology,” J. Comb. Chem., Vol. 3(2) (2001), at pp. 171-76. Spiro heterocycles are also disclosed in Couture et al., “Chemistry of Cyclic Aminooxycarbenes,” Can. J. Chem., Vol. 75(9) (1997) at pp. 1281-1294; Brandstetter et al., “Glucofuranose Analogs of Hydantocidin,” Tetrahedron, Vol. 52(32) (1996), at pp. 10721-10736; Brandstetter et al., “Spirohydantoins of Glucofuranose: Analogs of Hydantocidin,” Tetrahedron Lett., Vol. 36(12) (1995) at pp. 2149-52; in U.S. Pat. Nos. 6,022,875, 4,241,208, 4,066,615, and 3,941,744, and International patent application WO 01/45704. WO 01/94346 discloses 1,3,8-triaza-spiro′4,5 decan-4-one derivatives as neurokinin receptor antagonists.
Each of the patents, patent applications and publications referenced above and hereinafter is incorporated herein by reference.